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Terra,
Derek's Immune sytem is now building up an army of Cytotoxic T-cells to destroy the tumors. This army is going to need some food (Growth factor) to keep fighting. Derek's may be able to produce this growth factor (IL-2) on it s own.
If the the shrinkage stopes before all the tumors are eradicated, he may want to reintroduce Yervoy and or HD IL-2.
The Shrinkage can sometimes take over 200 days to fully eradicated the tumors.
Why Does Yervoy need to be systematically combined with IL-2?
Yervoy therapy acts upon the T-cells by blocking the CTLA-4 receptor, making it unable to engage. By doing this blockade, the CD28/B7 complex can engage and the signaling to activate, secrete and multiply is allowed. Cytokines produced by activated cells can stimulate or inhibit the production of other cytokines by the same cells in an autocrine manner or those present in the vicinity by a paracrine mechanism. Thus, a complex network of cell interactions is established, with positive and negative feedback controls, regulating cytokine production. For example,
TNF-a induces the synthesis of both IL-1 and IL-6 in macrophages. In contrast, IL-10, which is also synthesized by macrophages, inhibits the synthesis of TNF-a, IL-1 and IL-6. Both IFN-g and TNF-a can activate macrophages, which subsequently synthesize TNF-a and IL-1. What I am trying to elude to is that depending on the microenvironment which contains many cytokines, the pattern of cytokines matters whether the macrophages are activated or not.
This does not take into account the suppressiveness of the Tumor’s activity. Melanoma tumors can secrete TGF-b and IL-10 and other suppressive molecules. These suppressive cytokines (IL-10) can block the activation of the tumor associated macrophages (TAMs) which in turn inhibits the secretion of other cytokines and chemoattractants into the Tumor’s microenvironment. This inhibition suppresses the “Danger Signal” needed to alarm the immune system of foreign invaders (Tumor cells).
Th1 cells promote macrophage activation by producing IL-2 and IFN-g. What if the Th1 cells are not producing enough or there are many Tregs in the tumor’s microenvironment recruited by the tumors themselves? The Tregs, Th1 and the CD8+ T-cells are all competing for the IL-2 for survival. There could be a shortage of IL-2 to satisfy all the cells leading to a less than robust response. It has been greatly accepted that macrophage activation by IL-2 is essential for tumor regression. et al Masztalerz
So administration of HD IL-2 during the peak propagation of the (ALC) Absolute Lymphocyte Count (7 weeks or 49 days) may be synergetic to Yervoy.
Congrats on the Derek's immune response.
Warm regards,
Jimmy B
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Terra,
Derek's Immune sytem is now building up an army of Cytotoxic T-cells to destroy the tumors. This army is going to need some food (Growth factor) to keep fighting. Derek's may be able to produce this growth factor (IL-2) on it s own.
If the the shrinkage stopes before all the tumors are eradicated, he may want to reintroduce Yervoy and or HD IL-2.
The Shrinkage can sometimes take over 200 days to fully eradicated the tumors.
Why Does Yervoy need to be systematically combined with IL-2?
Yervoy therapy acts upon the T-cells by blocking the CTLA-4 receptor, making it unable to engage. By doing this blockade, the CD28/B7 complex can engage and the signaling to activate, secrete and multiply is allowed. Cytokines produced by activated cells can stimulate or inhibit the production of other cytokines by the same cells in an autocrine manner or those present in the vicinity by a paracrine mechanism. Thus, a complex network of cell interactions is established, with positive and negative feedback controls, regulating cytokine production. For example,
TNF-a induces the synthesis of both IL-1 and IL-6 in macrophages. In contrast, IL-10, which is also synthesized by macrophages, inhibits the synthesis of TNF-a, IL-1 and IL-6. Both IFN-g and TNF-a can activate macrophages, which subsequently synthesize TNF-a and IL-1. What I am trying to elude to is that depending on the microenvironment which contains many cytokines, the pattern of cytokines matters whether the macrophages are activated or not.
This does not take into account the suppressiveness of the Tumor’s activity. Melanoma tumors can secrete TGF-b and IL-10 and other suppressive molecules. These suppressive cytokines (IL-10) can block the activation of the tumor associated macrophages (TAMs) which in turn inhibits the secretion of other cytokines and chemoattractants into the Tumor’s microenvironment. This inhibition suppresses the “Danger Signal” needed to alarm the immune system of foreign invaders (Tumor cells).
Th1 cells promote macrophage activation by producing IL-2 and IFN-g. What if the Th1 cells are not producing enough or there are many Tregs in the tumor’s microenvironment recruited by the tumors themselves? The Tregs, Th1 and the CD8+ T-cells are all competing for the IL-2 for survival. There could be a shortage of IL-2 to satisfy all the cells leading to a less than robust response. It has been greatly accepted that macrophage activation by IL-2 is essential for tumor regression. et al Masztalerz
So administration of HD IL-2 during the peak propagation of the (ALC) Absolute Lymphocyte Count (7 weeks or 49 days) may be synergetic to Yervoy.
Congrats on the Derek's immune response.
Warm regards,
Jimmy B
-
Terra,
Derek's Immune sytem is now building up an army of Cytotoxic T-cells to destroy the tumors. This army is going to need some food (Growth factor) to keep fighting. Derek's may be able to produce this growth factor (IL-2) on it s own.
If the the shrinkage stopes before all the tumors are eradicated, he may want to reintroduce Yervoy and or HD IL-2.
The Shrinkage can sometimes take over 200 days to fully eradicated the tumors.
Why Does Yervoy need to be systematically combined with IL-2?
Yervoy therapy acts upon the T-cells by blocking the CTLA-4 receptor, making it unable to engage. By doing this blockade, the CD28/B7 complex can engage and the signaling to activate, secrete and multiply is allowed. Cytokines produced by activated cells can stimulate or inhibit the production of other cytokines by the same cells in an autocrine manner or those present in the vicinity by a paracrine mechanism. Thus, a complex network of cell interactions is established, with positive and negative feedback controls, regulating cytokine production. For example,
TNF-a induces the synthesis of both IL-1 and IL-6 in macrophages. In contrast, IL-10, which is also synthesized by macrophages, inhibits the synthesis of TNF-a, IL-1 and IL-6. Both IFN-g and TNF-a can activate macrophages, which subsequently synthesize TNF-a and IL-1. What I am trying to elude to is that depending on the microenvironment which contains many cytokines, the pattern of cytokines matters whether the macrophages are activated or not.
This does not take into account the suppressiveness of the Tumor’s activity. Melanoma tumors can secrete TGF-b and IL-10 and other suppressive molecules. These suppressive cytokines (IL-10) can block the activation of the tumor associated macrophages (TAMs) which in turn inhibits the secretion of other cytokines and chemoattractants into the Tumor’s microenvironment. This inhibition suppresses the “Danger Signal” needed to alarm the immune system of foreign invaders (Tumor cells).
Th1 cells promote macrophage activation by producing IL-2 and IFN-g. What if the Th1 cells are not producing enough or there are many Tregs in the tumor’s microenvironment recruited by the tumors themselves? The Tregs, Th1 and the CD8+ T-cells are all competing for the IL-2 for survival. There could be a shortage of IL-2 to satisfy all the cells leading to a less than robust response. It has been greatly accepted that macrophage activation by IL-2 is essential for tumor regression. et al Masztalerz
So administration of HD IL-2 during the peak propagation of the (ALC) Absolute Lymphocyte Count (7 weeks or 49 days) may be synergetic to Yervoy.
Congrats on the Derek's immune response.
Warm regards,
Jimmy B
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